Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase

Bredt, David S.; Hwang, Paul M.; Glatt, Charles E.; Lowenstein, Charles J.; Reed, Randall R.; Snyder, Solomon H.

doi:10.1016/0962-8924(91)90032-5

Cited by 468 publications

(613 citation statements)

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“…The large number of available flavodoxin sequences offers a good starting set for the reciprocal screen. Using a profile derived from the flavodoxin family, the 3 sequences rank (Z scores 4.9-7.3) among or above known FMN-binding proteins ) whose homology to flavodoxins has been already discussed: the NADPH-cytochrome P450 reductase (Porter et al, 1990), the nitric-oxide synthase (Bredt et al, 1991), the sulfite reductase a-component (Ostrowski et al, 1989), and the flavodoxin-like protein of Rhodobacter capsulatus (Jouanneau Y, 1990, Genbank entry X54054; Jouanneau et al, 1990).…”

Section: Homology Searchmentioning

confidence: 99%

“…Another long insertion in the WrbA family follows 02, but in this region the different members of the family d o not show high sequence similarity. YihB presents a long insertion after a 2 of the same length and at the same position as the nitric-oxide synthase from brain compared to the NADPH-cytochrome P450 reductase (Bredt et al, 1991) and to flavodoxins (not shown).…”

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confidence: 99%

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Six new candidate members of the α/β twisted open‐sheet family detected by sequence similarity to flavodoxin

Grandori

Carey

1994

Protein Science

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We discuss sequence conservation with reference to the known 3-dimensional structures of flavodoxins. Conserved sequence and hydrophobicity patterns, as well as residue-pair interaction potentials, strongly support the hypothesis that these proteins share the a//3 twisted open-sheet fold typical of flavodoxins, with an additional unit in the WrbA family. On the basis of the proposed structural homology, we discuss the details of the putative FMNbinding sites. Our analysis also suggests that the helix-turn-helix motif we identified previously in the C-terminal region of the WrbA family is unlikely to reflect a DNA-binding function of this new protein family.

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Section: Homology Searchmentioning

confidence: 99%

mentioning

confidence: 99%

Six new candidate members of the α/β twisted open‐sheet family detected by sequence similarity to flavodoxin

Grandori

Carey

1994

Protein Science

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“…The three NOS isoforms are neuronal NOS (nNOS; also known as brain NOS) that is located within nerve cells, endothelial NOS (eNOS) that is located within vessel endothelium, and inducible NOS (iNOS) that is found in macrophages, astroglia cells, and microglial cells. [1][2][3][4][5] When the spinal cord is injured, the tissue that surrounds the primary lesion is transformed into a secondary lesion. Reactive oxygen species (ROS) are important mediators of SCI.…”

Section: Introductionmentioning

confidence: 99%

Changes in nitric oxide synthase expression in young and adult rats after spinal cord injury

2007

Spinal Cord

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Objective: To examine the clinical meaning of the changes in nitric oxide synthase (NOS) expression and activity after spinal cord injury (SCI) according to the age of the experiment animal. Material and method: Ten 5-and 16-week-old Sprague-Dawley rats were laminectomized at T10 and SCI induced at this level using a New York impactor. Outcome measures to assess SCI utilized the Basso-Beatti-Bresnahan scale to quantitate hind limb motor dysfunction as a functional outcome measure. NOS isoforms (nNOS, neuronal NOS; iNOS, inducible NOS; and eNOS, endothelial NOS) were also immunolocalized in sections of control and spinal cord injury in the two sample groups using specific monoclonal antibodies. Student's t-test evaluated the difference between the young and adult rats, and Po0.05 was considered as significant value. Result: As the expression of nNOS on the spinal gray matter of the adult rat decreased, eNOS activity increased. Different from the adult rat, expression of the nNOS in the young rat was maintained until 1 day after SCI, and compared with the adult rat; eNOS activity was increased in the vessels from the damaged gray matter area after 7 days of SCI. iNOS expression was maintained until the 7th day of SCI on the adult rat, but iNOS expression after 7 days of SCI on young rat decreased. The young rat showed relatively less motor disability on the hind limb when compared with the adult rat, and had a rapid recovery. Conclusion: Neural protective eNOS activity increased after SCI in the young rat, and neural destructive iNOS expression was more remarkable in the adult rat.

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“…3 The intracellular Ca 2 þ triggers the generation of nitric oxide (NO) by activating neuronal NO synthase (nNOS) in a Ca 2 þ /calmodulin (CaM)-dependent manner. 4,5 Although physiological levels of NO contribute to preserving cellular functions, intense accumulation of nitrosative stress due to excessive generation of reactive nitrogen species (RNS) like NO is thought to play a causal role in neuronal cell damage and death. The discrepancy of NO effects on neuronal survival can also be caused by the formation of different NO species or intermediates: NO radical (NO Á ), nitrosonium cation (NO þ ), nitroxyl anion (NO À , with high-energy singlet and lower energy triplet forms).…”

mentioning

confidence: 99%

“…3,6,26,27,30,31 Ca 2 þ Influx and Generation of NO Increased levels of neuronal Ca 2 þ , in conjunction with the Ca 2 þ -binding protein CaM, trigger the activation of nNOS and subsequent generation of NO from the amino acid L-arginine ( Figure 1). 4 NO is a gaseous-free radical (thus highly diffusible) and a key molecule that plays a vital role in normal signal transduction but in excess can lead to neuronal cell damage and death. Three subtypes of NOS have been identified; two constitutive forms of NOS -nNOS and endothelial NOS -take their names from the cell type in which they were first found.…”

mentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase

Cited by 468 publications

References 0 publications

Six new candidate members of the α/β twisted open‐sheet family detected by sequence similarity to flavodoxin

Six new candidate members of the α/β twisted open‐sheet family detected by sequence similarity to flavodoxin

Changes in nitric oxide synthase expression in young and adult rats after spinal cord injury

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

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